This invention generally pertains to heterocyclic compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with the hemi-hydrate form of a cognition enhancing agent, 1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]-methyl]-2-pyrroli dinone. This agent is more commonly known as BMY-21502, although it is also designated BMS 181168.
BMY-21502 is an orally active agent for the treatment of memory and cognitive disorders including senile dementia and Alzheimer's disease. While its mechanism of action is not completely known, beneficial effects of BMY-21502 have been demonstrated in behavorial paradigms, autoradiographic studies, cell culture studies and electrophysiologic examination of hippocampal neurons in rat brain slices.
The hemi-hydrate form of BMY-21502, the compound of this invention is likewise a cerebral function enhancer useful in treating various dementias due to degenerative processes as well as in enhancing memory and learning.
The most relevant art is believed to be the patent to Mattson, et al., U.S. Pat. No. 4,826,843 issued May 2, 1989, wherein compounds of general formula (1) were disclosed as having cognition and memory enhancing activities. ##STR1##
For formula (1), X is an ethylene chain or 1,2-benzo ring; Y is carbonyl or methylene; R.sup.1 is hydrogen or lower alkyl; and Z is an R.sup.2, R.sup.3 -disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems. A preferred compound of the series was 1-[[1[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]-methyl]-2-pyrrolid inone (1a), hereinafter referred as BMY-21502. ##STR2##
BMY-21502 has been under clinical evaluation for the treatment of memory and cognitive disorders.
Other related art comprises oxygenated derivatives of BMY-21502 disclosed in U.S. Pat. No. 5,098,904 issued Mar. 24, 1992 to Mattson, et al. and an improved synthetic process for producing BMY-21502 which was disclosed in U.S. Pat. No. 4,963,678 issued Oct. 16, 1990 to Mattson, et al.
Although solvates such as hydrates were disclosed in general terms for formula (1) compounds by Mattson, et al. in U.S. 4,826,843, there has been no prior disclosure or appreciation of the useful novel hemi-hydrate form of BMY-21502 which constitutes the present invention. A major advantage of the hemi-hydrate form of BMY-21502 relates to increased efficiency and safety in manufacture of the hemi-hydrate compound over the anhydrous form which was specifically disclosed in the prior art.